Neurological disease has been one of the prevalent diseases in contemporary society. However, many types of neurological disease have not yet been effectively addressed in clinical practice. Especially, the treatments for neurological diseases such as schizophrenia, Parkinson's disease and the like are still far from achieving a satisfactory result.
Schizophrenia is one of the most serious mental disorders, and has an incidence of up to 1% in a general population. Its clinical manifestation may be classified into positive symptoms represented by hallucination, delusion, exhilaration, bizarre behavior, etc., and negative symptoms represented by quiet, poverty of thought, abepithymia, abulia, degeneration of sociability etc. According to incomplete statistics, China has no less than 10 million of patients with schizophrenia. As the pace of life is quickened and the pressure of work is increased, schizophrenia tends to have an increasing incidence, and will cause heavy economic burden and social burden.
The recognition of the mechanism of schizophrenia was firstly originated from the use of chlorpromazine about half a century ago. In the practice of treating schizophrenia, blocking dopamine (DA) D2 receptor in brain is deemed as the main direction of drug research against schizophrenia. Based on such recognition, the pathological DA theory of schizophrenia was established. The first-generation drugs against schizophrenia, as DA antagonists, have relatively serious side effect to extrapyramidal system and hyperpro lactinemia due to its lacking of selectivity to DA receptor. With progression in cognition about the pathology of schizophrenia and research on cloning of the subtypes of DA receptor and difference in their pharmacologic characteristics, the second-generation antipsychotic drugs, which are also referred as nonclassical antipsychotic drugs, were developed. The representative examples of these drugs include Clozapine, Risperidone and so on, which share the similar characteristics of having an increased selectivity to D2 acceptor antagonistic action and a weaker side effect than the first-generation antipsychotic drugs. These drugs can effectively improve the patients' positive symptoms including delusion, hallucination and so on, but still have weak activity on treating the negative symptoms of schizophrenia. Thus, there is a urgent need to design and develop new antipsychotic drugs.
The normal function of brain depends on appropriate amount of DA and its normal activity. It has been known that overactivity, especially the hyperfunction, of DA receptor, is related to the positive symptoms of schizophrenia, such as delusion, hallucination and the like, and abnormal activity of nigrostriatal DA is related to extrapyramidal symptoms. The occurrence of the negative symptoms of schizophrenia and damage to cognitive function are related to DA activity, especially impairment of D1/NMDA receptors, in prefrontal cortex (mPFC), wherein hypofrontality of D1 in mPFC may be the key point. Due to hypofrontality of DA in this area, the inhibitory effect to nucleus accumbens (NAc) and ventral tegmental area (VTA) is reduced, and thus hyperfunction of DA in subcortex region is incurred, resulting in the positive symptoms of schizophrenia. Meanwhile, impairment to D1/NMDA receptors, including 5-HT receptor, in mPFC is closely related to negative symptoms and cognitive function. It has been proved that there is an interadjusting between D1 and NMDA receptor. Thus, disorder and imbalance of DA functional activities in certain encephalic region, i.e., hypofrontality of D1/NMDA in mPFC area, and hyperfunction of D2 in subcortical structures are considered as the current pathomechanism of schizophrenia. Therefore, rebuilding and recovering the balance of DA activity in brain naturally becomes a new therapeutic strategy of schizophrenia. Accordingly, it is an ideal orientation for the study on antischizophrenic drugs to research and develop drugs capable of recovering and stabilizing the normal activity of DA. Meanwhile, by caning out working memory experiments for animals and patients, short-term experiments reflecting the function of medical prefrontal cortex, as well as clinical trials, it has been demonstrated that the inactivation of D1 receptor is related to negative symptoms of schizophrenia, and high activity of D2 receptor generates the positive symptoms. Based on such hypothesis, if a drug can effectively activate the activity of D1 receptor and antagonize the activity of D2 receptor at the same time, such a drug will have a good prospect for the treatment of schizophrenia. However, the currently known antipsychotic drugs are mainly based on antagonism against D2 receptor, and thus have poor therapeutic effect on negative symptoms. In particular, such drugs cannot function to stabilize and recover normal DA activity in brain. Therefore, it is of great significance to develop new antipsychotic drugs having a dual function of D1 agonistic and D2 antagonistic activity and further balancing DA activities,
Parkinson's disease is a chronic progressive degenerative disorder, which is mainly characterized by the dopaminergic neuron loss in the substantia nigra. For a long time, L-Dopamine is a “gold standard” for the treatment of Parkinson's disease. However, long-term administration of L-Dopamine is often accompanied by high incidence of treatment-related complication, such as dyskinesias, efficacy loss and “on-off” phenomenon and the like, which are named as “L-Dopamine long-term syndrom”, and the disease progression can not be delayed.
DA receptor agonist is one of various substitutive therapies for Parkinson's disease and mainly used with L-Dopamine in Parkinson's having dyskinesia. DA receptor agonist is superior to L-Dopamine for the following mechanism. In the later stage of Parkinson's disease, since dopamine decarboxylase activity of the nigrostriatal dopaminerigic system is depleted, exogenous L-Dopamine can not be transformed into DA through decarboxylation, and at this time, even a large dose of L-Dopamine preparation is ineffective. However, the function of DA receptor agonist is irrelevant to DA synthesis and does not depend on the activity of dopadecarboxylase. It has a molecular conformation similar to that of DA, and directly acts on the striatal synaptic DA receptor, primarily D1 receptor, and partially functions through D2 receptor. Therefore, the combination of DA receptor agonist can further improve the motor symptoms of Parkinson's disease. Based on such theory, if a D1 receptor agonist with selectivity is developed, it will be possible to provide a class of drugs with good effect for the treatment of Parkinson's disease. So far, many D1 receptor agonists with selectivity have been developed in various large companies, and many of them are in clinical trails. However, many drug candidates have low selectivity and obvious side effects. Therefore, it will undoubtedly have huge advantages and provide wide space for the treatment of Parkinson's disease to develop a D1 receptor selective agonist with high selectivity and little side effect.
Diarylo[a,g]quinolizines have a common chemical core structure, and various biological activities, including anti-inflammatory effect, antibacterial effect, anti-leukemia effect, anti-cancer effect and so on. Jin Guozhang, an academician of Chinese Academy of Sciences, together with others systematically studied the pharmacological activities of 6H-dibenzo[a,g]quinolizines and confirmed that levorotatory tetrahydropalmatine has good analgesic effect with sedation, tranquilizing and hypnotic effects, while dextrorotatory tetrahydropalmatine has no significant analgesic effect. It is also confirmed that levorotatory tetrahydropalmatine and other 6H-dibenzo[a,g]quinolizine alkaloids target the dopamine receptor. Jin Guozhang also first reported that 1-Stepholidine (1-SPD), one of 6H-dibenzo[a,g]quinolizines (THPBs), is the first leading compound having the dual function of D1 agonistic and D2 antagonistic activity (Jin G. Z. TIPS, 2002, 23-24). Clinical trial demonstrated that 1-SPD had good therapeutic effects on both the positive and negative symptoms with non-classical stabilizer features, and thus could be likely developed into a new class of antipsychotic drugs. Shen Jingshan, Yang Yushe et al. disclosed levorotatory Chloroscoulerine and 1-SPD derivatives with antipsychotic effect, and preparation methods and uses thereof, and especially levorotatory Scoulerine methanesulfonate with good water solubility and stability (WO2008/014661, CN03151464, and CN1900076). However, these compounds have a structure which has little room to be modified, and most of them have weak activity on D2 receptor, and many of them have no 5-HT activity with poor solubility and low bioavailability. Meanwhile, these compounds showed a certain degree of selectivity in D1 receptor vs D2 receptor. Therefore, it is of significance to continually modify diarylo[a,g]quinolizines, especially to develop a compound with better D2 activity or a D1 receptor agonist with better selectivity, thereby providing beneficial help for the treatment of Parkinson's disease.
The present invention provides a class of diarylo[a,g]quinolines with novel structures, and the synthesis and use thereof. Some of the compounds with such structure show good selectivity for D1 vs D2, and many of the compounds also have 5-HT activity. In addition, some of the compounds have dual pharmacological activities of good D1 agonist and D2 antagonist with good solubility, and can be used in the preparation of a medicament for treating neurological disease, especially those associated with dopamine receptors and serotonin receptor.